1. Field of Invention
This invention relates to a carrier base material to be combined with a therapeutically active medicament and formed into a solid shaped dosage unit having a long-lasting and regular incremental release of the medicament upon administration. Specifically, this invention relates to a carrier base material, consisting essentially or predominantly of hydroxypropylmethylcellulose having a chemical structure and molecular weight which renders it suitable for use in prolonged release therapeutic compositions.
2. Description of the Prior Art
Hydroxypropylmethylcelluloses are commercially available in various grades, under several tradenames, including Methocel E, F, J and K (all previously designated as Methocel HG) from The Dow Chemical Co., U.S.A., HPM from British Celanese, Ltd., England, and Metalose SH from Shin-Etsu, Ltd., Japan. The various grades available under a given tradename represent differences in methoxy and hydroxypropoxyl content as well as molecular weight. The methoxyl content ranges from 16.5 to 30 weight-% and the hydroxypropoxyl content ranges from 4 to 32 weight-%, as determined by the method described in ASTM D-2363-72.
Commercial designations of the various hydroxypropylmethylcelluloses are based on the viscosities of 2% aqueous solutions at 20.degree. C. The viscosities range from 15 cps to 30,000 cps and represent number average molecular weights (Mn) ranging from about 10,000 to over 150,000.
Christenson and Dale (U.S. Pat. No. 3,065,143) disclosed the use of certain hydrophilic gums, including hydroxypropylmethylcelluloses, in the preparation of a "sustained release tablet". The tablet consisted essentially of a mixture of a medicament and at least one third part by weight of the weight of the tablet of a hydrophilic gum which rapidly absorbed water and swelled at 37.degree. C. to form a "soft mucilaginous gel barrier" on the surface of the tablet when brought into contact with the aqueous fluids of the gastro-intestinal tract.
The ability to form a "soft mucilaginous gel" on contact with aqueous fluids is dependent upon the molecular weight of the hydrophilic gum including hydroxypropylmethylcelluloses. The need to use high molecular weight polymers is evident from the disclosures of those which are effective in the practice of the invention of U.S. Pat. No. 3,065,143. Thus, Examples 1 and 7 disclose the use of Methocel 60HG 4000 cps, Example 4 discloses the use of Methocel 90HG 4000 cps, and Example 5 discloses the use of Methocel 90HG 15,000 cps.
Methocel 60HG 4000 cps, now known as Methocel E4M, has a 28-30 weight-% methoxyl content and a 7.5-12 weight-% hydroxypropoxyl content. The 4000 cps viscosity grade indicates that the polymer has a number average molecular weight of 93,000, as calculated from the data in "Handbook of Methocel Cellulose Ether Products" (The Dow Chemical Co., 1974).
Methocel 90HG 4000 cps and Methocel 90HG 15,000 cps, now known as Methocel K4M and Methocel K15M, respectively, have a 19-24 weight-% methoxyl content and a 4-12 weight-% hydroxypropoxyl content. The 4000 cps and 15,000 cps viscosities indicate that the polymers have number average molecular weights of 89,000 and 124,000, respectively.
The other examples in U.S. Pat. No. 3,065,143 disclose the use of "extra high viscosity" sodium carboxymethylcellulose and carboxypolymethylene, both having high molecular weights, as effective hydrophilic gums. In contrast, Example 1 discloses that 400 cps methylcellulose is ineffective in the practice of the invention. This polymer has a number average molecular weight of 41,000 ("Handbook of Methocel Cellulose Ether Products", loc. cit.).
Christenson and Huber (U.S. Pat. No. 3,590,117) reported that high viscosity, i.e. 15,000 cps, hydroxypropylmethylcellulose did not make an acceptable long-lasting troche because the troche would flake off in the mouth rather than dissolve uniformly. "Low viscosity" hydroxypropylmethylcellulose yielded unacceptable troches because they generated extremely viscous and adhesive saliva which resulted in a gagging response (column 1, lines 29-47).
The use of modified lower molecular weight hydroxypropylmethylcellulose, per se and in admixture with either ethylcellulose or sodium carboxymethylcellulose, as a carrier base in sustained release pharmaceutical compositions is disclosed by Lowey and Stafford (U.S. Pat. No. 3,870,790) and Schor (U.S. Pat. No. 4,226,849). The Methocel E50 disclosed in these patents was formerly known as Methocel 60HG 50 cps and has a number average molecular weight of 23,000. However, the polymer is modified for use in sustained release solid dosage units by exposure to high humidity or moisture and drying in a current of air.
The present invention is directed toward further improvements in carrier bases containing hydroxypropylmethylcelluloses for use in the preparation of solid pharmaceutical unit dosages which have sustained release.